Autoregulatory Ability Research Articles

The LpHsfA2-molecular module confers thermotolerance via fine tuning of its transcription in perennial ryegrass (Lolium perenne L.).

Temperature sensitivity and tolerance play a key role in plant survival and production. Perennial ryegrass (Lolium perenne L.), widely cultivated in cool-season for forage supply and turfgrass, is extremely susceptible to high temperatures, therefore serving as an excellent grass for dissecting the genomic and genetic basis of high-temperature adaptation. In this study, expression analysis revealed that LpHsfA2, an important gene associated with high-temperature tolerance in perennial ryegrass, is rapidly and substantially induced under heat stress. Additionally, heat-tolerant varieties consistently display elevated expression levels of LpHsfA2 compared with heat-sensitive ones. Comparative haplotype analysis of the LpHsfA2 promoter indicated an uneven distribution of two haplotypes (HsfA2Hap1 and HsfA2Hap2) across varieties with differing heat tolerance. Specifically, the HsfA2Hap1 allele is predominantly present in heat-tolerant varieties, while the HsfA2Hap2 allele exhibits the opposite pattern. Overexpression of LpHsfA2 confers enhanced thermotolerance, whereas silencing of LpHsfA2 compromises heat tolerance. Furthermore, LpHsfA2 orchestrates its protective effects by directly binding to the promoters of LpHSP18.2 and LpAPX1 to activate their expression, preventing the non-specific misfolding of intracellular protein and the accumulation of reactive oxygen species in cells. Additionally, LpHsfA4 and LpHsfA5 were shown to engage directly with the promoter of LpHsfA2, upregulating its expression as well as the expression of LpHSP18.2 and LpAPX1, thus contributing to enhanced heat tolerance. Markedly, LpHsfA2 possesses autoregulatory ability by directly binding to its own promoter to modulate the self-transcription. Based on these findings, we propose a model for modulating the thermotolerance of perennial ryegrass by precisely regulating the expression of LpHsfA2. Collectively, these findings provide a scientific basis for the development of thermotolerant perennial ryegrass cultivars.

Mitochondria and renal microvascular dysfunction following ischemia-reperfusion in rats

The pathophysiological mechanisms underlying ischemia-reperfusion (IR) induced acute kidney injury (AKI) remain poorly understood. Preglomerular microvessels (PGMV), specifically afferent arterioles, possess an intrinsic autoregulatory ability that is vital for ensuring stable renal hemodynamics. Our recent study indicates that renal autoregulation is impaired in IR rats due to reactive oxygen species (ROS) accumulation. We hypothesized that mitochondria-derived ROS (mtROS) in preglomerular microvessels contribute to renal autoregulatory impairment in IR rats. Blood-perfused juxtamedullary nephron experiments were performed on kidneys of male Sprague-Dawley rats 24 hours after IR induction (60-min, bilateral renal artery clamping). Afferent arteriolar autoregulation was assessed as perfusion pressure (PP) was increased from 65 to 170 mmHg in 15 mmHg increments. Afferent arterioles of sham-operated control rats (n=7) established pressure-mediated autoregulatory responses. Baseline diameter (100 mmHg) averaged 13.2±0.4 μm and increased to 114±4% of baseline when PP decreased from 100 to 65 mmHg. Diameter decreased to 65±3% of baseline when PP increased to 170 mmHg. In contrast, afferent arterioles from IR rats lost autoregulatory capability and remained between 90 and 100% of baseline diameter over 65-170 mmHg (n=8). Addition of Mito-Tempo (mitochondria-targeted antioxidant, 0.1 mM, n=3) to the perfusate restored autoregulation in IR rats at lower PP (65-125 mmHg, P>0.05 vs sham) and partially restored it over 140-170 mmHg. Superfusion with oligomycin (ATP synthase inhibitor, 2.5 μM) in normal kidneys evoked vasodilation to 178±13% baseline and blunting of autoregulatory reactivity. Renal autoregulation is linked to ATP-sensitive P2X1-receptor signaling. Changes in ATP-induced intracellular calcium concentration ([Ca2+]i) were assessed in isolated PGMV myocytes using Fura-2 fluorescent dye. IR markedly attenuated [Ca2+]i responses to 10 and 100 μM ATP by 46±11% and 57±15%, respectively (P<0.05, n=3-4 rats/group), and blunted ATP-induced afferent arteriolar vasoconstriction ( P<0.05 vs. sham, n=3/group). IR markedly increased the fluorescence intensity of mitoROS (MitoSOX™ kit) in PGMV compared to sham rats. Mitochondrial respiratory function was assessed using High Resolution Respirometry in freshly isolated PGMV (n=3/group). IR significantly reduced basal respiration (20±4 vs. 58±9 pmol/s·ml in sham, P<0.05) and oxidative phosphorylation capacity (51±10 vs. 219±37 pmol/s·ml in sham, P<0.05). The percentage of ATP-linked respiration was also reduced in PGMV of IR (60±2% vs. 75±2% in sham, P<0.05). In conclusion, mitochondria of PGMV are involved in regulating renal microvascular tone and autoregulation. IR leads to autoregulatory dysfunction by causing mitochondrial dysfunction in PGMV, increased mtROS production and suppression of ATP-dependent calcium signaling. This study is supported by grants R01DK106500. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Using the FOCUS Family Intervention for Family-Centered Care in a Premature Infant With Grade IV Intraventricular Hemorrhage

Preterm infants face increased rates of mortality and developmental complications, which are a burden on children's parents (and caregivers), who suffer from exhaustion and situational uncertainty. This case focused on an extremely-low-birth-weight (908 gm) premature infant with initial unstable vital signs complicated by a grade 4 intraventricular hemorrhage (IVH) that led to partial brain atrophy and enlarged brain ventricles. A poor neurological outcome was expected due to the high risk of cerebral palsy and impaired cognitive abilities. Long-term healthcare for this critical infant was causing tremendous physical, emotional, and financial strains on the family. The parents suffered from worries over the poor prognosis, resulting in stress, sleep disorders, and relationship difficulties with the healthcare professionals. Considering the poor prognosis of the infant, the parents faced a medical dilemma between choosing aggressive treatment and withdrawal of treatment, which led to stress and sleep disorders. Differences between the parents and health professionals regarding disease severity perception and treatment opinions further strained their mutual relationship. To ameliorate this issue, the author implemented family-centered care (the FOCUS family intervention) to help the patient and his family. This intervention is designed to increase family involvement, foster an optimistic attitude and effective stress coping techniques, and reduce uncertainty and negative emotions. For the patient, we provided symptom-relief management to improve abnormal muscle tone and development delay. Our intervention ameliorated the negative emotions, insomnia symptoms, and imbalanced family relationships and improved the life quality of the caregivers. Furthermore, the intervention enhanced the patient's autoregulatory ability, and both physical and neurological development. This case study is expected to provide experience in critical care for premature infants with a poor prognosis and their family using a FOCUS family intervention as well as to improve the quality of healthcare delivery in intensive clinical settings.

Klotho Ameliorates Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys.

Renal expression of klotho is reduced in hypertension. Experiments were performed to examine whether exogenous klotho protein supplementation ameliorates pressure natriuresis in early phase of hypertension, using stroke-prone spontaneously hypertensive rats (sp-SHR). The interactions between klotho protein and renal renin-Ang (angiotensin) system were examined with immunoprecipitation and cell culture methods. Uninephrectomy was performed in sp-SHRs to induce nephrosclerosis, and they were treated with exogenous klotho protein or vehicle. Exogenous klotho protein supplementation to sp-SHR decreased blood pressure, renal Ang II levels, AGT (angiotensinogen) expression, HIF (hypoxia-inducible factor)-1α abundance, and medullary fibronectin levels, with increased renal klotho expression and serum and urine klotho levels. Klotho supplementation also reduced kidney weight, renal phosphorylated Akt, and mTOR (mammalian target of rapamycin) abundance. Furthermore, klotho supplementation restored renal autoregulation of glomerular filtration rate and enhanced pressure-induced natriuresis in sp-SHR. Klotho protein bound to AT1R (Ang II type-1 receptor) and decreased the presence of AT1R on HK-2 (human proximal tubular) cells, attenuating inositol triphosphate generation. Klotho protein suppressed Ang II-induced increments of AGT expression in HK-2 cells. Collectively, the present data demonstrate that klotho binds with the AT1R to suppress Ang signal transduction, participating in inactivating renal renin-Ang system. Our results also suggest that exogenous klotho supplementation represses Akt-mTOR signaling to reduce renal hypertrophy and restore the autoregulatory ability of glomerular filtration rate in uninephrectomized sp-SHRs. Finally, the present findings implicate that klotho supplementation inhibits HIF-1α pathway and medullary fibrosis, contributing to enhancements of pressure natriuresis and reduction in blood pressure.

Abstract P419: Klotho Ameliorate Medullary Fibrosis and Pressure Natriuresis in Hypertensive Rat Kidneys

Recent data indicate that klotho interacts with the renin-angiotensin system (RAS). However, the effects of klotho protein supplementation on hypertensive renal injury have not been examined yet. First, the in vivo experiments were performed using spontaneously hypertensive rats (SHR). To elucidate in vivo observations, the in vitro studies were carried out to examine the interactions between klotho protein and angiotensin type-1 (AT1) receptor with immunoprecipitation and cell culture (HK-2 cell) methods. Uninephrectomized SHRs were treated with exogenous klotho protein or vehicle. Exogenous klotho protein supplementation to uninephrectomized SHRs decreased blood pressure, renal angiotensin II levels, angiotensinogen expression, HIF-1α abundance, and medullary fibronectin with increased renal klotho expression and serum and urine klotho levels. Klotho supplementation also reduced kidney weight, renal phosphorylated Akt and mTOR abundance. Furthermore, klotho supplementation restored renal autoregulation of glomerular filtration rate and renal plasma flow, and improved pressure-induced natriuresis in SHR. Klotho protein bound to AT1 receptors without affecting the bindings of angiotensin II to AT1 receptor. Klotho decreased the presence of AT1 receptors on HK-2 cells, attenuating inositol triphosphate generation. Angiotensin II elevated angiotensinogen expression in HK-2 cells, and klotho protein suppressed angiotensin II-induced increases in angiotensinogen expression. Of note, although angiotensin II improves glomerular autoregulatory ability especially at lower pressure range, angiotensin II impairs pressure-induced natriuresis. Collectively, the present data demonstrate that klotho binds with the AT1 receptors to suppress angiotensin signal transduction and inactivate the renal RAS. In addition, our results suggest that exogenous klotho supplementation suppresses Akt-mTOR signaling to decline renal hypertrophy and restores renal autoregulatory ability in uninephrectomized SHRs. Finally, the present findings implicate that klotho supplementation inhibits HIF-1α pathway to suppress medullary fibrosis, presumably involved in improvements of pressure-natriuresis and reduction in blood pressure.

Central blood pressure and chronic kidney disease.

In this review, we focused on the relationship between central blood pressure and chronic kidney diseases (CKD). Wave reflection is a major mechanism that determines central blood pressure in patients with CKD. Recent medical technology advances have enabled non-invasive central blood pressure measurements. Clinical trials have demonstrated that compared with brachial blood pressure, central blood pressure is a stronger risk factor for cardiovascular (CV) and renal diseases. CKD is characterized by a diminished renal autoregulatory ability, an augmented direct transmission of systemic blood pressure to glomeruli, and an increase in proteinuria. Any elevation in central blood pressure accelerates CKD progression. In the kidney, interstitial inflammation induces oxidative stress to handle proteinuria. Oxidative stress facilitates atherogenesis, increases arterial stiffness and central blood pressure, and worsens the CV prognosis in patients with CKD. A vicious cycle exists between CKD and central blood pressure. To stop this cycle, vasodilator antihypertensive drugs and statins can reduce central blood pressure and oxidative stress. Even in early-stage CKD, mineral and bone disorders (MBD) may develop. MBD promotes oxidative stress, arteriosclerosis, and elevated central blood pressure in patients with CKD. Early intervention or prevention seems necessary to maintain vascular health in patients with CKD.

Static autoregulation in humans: a review and reanalysis

IntroductionCerebral autoregulation (CA) is a theoretical construct characterized by the relationship between mean arterial pressure (MAP) and cerebral blood flow (CBF). We performed a comprehensive literature search to provide an up-to-date review on the static relationship between MAP and CBF. MethodsThe results are based on 40 studies (49 individual experimental protocols) in healthy subjects between 18 and 65 years. Exclusion criteria were: a ΔMAP <5%, hypoxia/hyperoxia or hypo/hypercapnia, and unstable levels (<2min stages). The partial pressure of arterial CO2 (PaCO2) was measured in a subset of the included studies (n=28); therefore, CBF was also adjusted to account for small changes in PaCO2. ResultsThe linear regression coefficient between MAP and CBF (or velocity) of 0.82±0.77%ΔCBF/%ΔMAP during decreases in MAP (n=23 experiments) was significantly different than the relationship of 0.21±0.47%ΔCBF/%ΔMAP during increases (n=26 experiments; p<0.001). After correction for increases/decreases in PaCO2, the slopes were not significantly different: 0.64±1.16%ΔCBF/%ΔMAP (n=16) and 0.39±0.30%ΔCBF/%ΔMAP (n=12) for increased vs. decreased MAP changes, respectively (p=0.60). ConclusionThe autoregulatory ability of the cerebral circulation appears to be more active in buffering increases in MAP as compared to reductions in MAP. However, the statistical finding of hysteresis is lost following an attempt to correct for PaCO2.

Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension.

This study tested the hypothesis that P2Y12 receptor blockade with clopidogrel preserves renal autoregulatory ability during ANG II-induced hypertension. Clopidogrel was administered orally to male Sprague-Dawley rats chronically infused with ANG II. After 14 days of treatment, whole kidney autoregulation of renal blood flow was assessed in vivo in pentobarbital-anesthetized rats using an ultrasonic flow probe placed around the left renal artery. In ANG II-vehicle-treated rats, decreasing arterial pressure over a range from 160 to 100 mmHg resulted in a 25 ± 5% decrease in renal blood flow, demonstrating a significant loss of autoregulation with an autoregulatory index of 0.66 ± 0.15. However, clopidogrel treatment preserved autoregulatory behavior in ANG II-treated rats to levels indistinguishable from normotensive sham-operated (sham) rats (autoregulatory index: 0.04 ± 0.14). Compared with normotensive sham-vehicle-treated rats, ANG II infusion increased renal CD3-positive T cell infiltration by 66 ± 6%, induced significant thickening of the preglomerular vessels and glomerular basement membrane and increased glomerular collagen I deposition, tubulointerstitial fibrosis, damage to the proximal tubular brush border, and protein excretion. Clopidogrel significantly reduced renal infiltration of T cells by 39 ± 9% and prevented interstitial artery thickening, ANG II-induced damage to the glomerular basement membrane, deposition of collagen type I, and tubulointerstitial fibrosis, despite the maintenance of hypertension. These data demonstrate that systemic P2Y12 receptor blockade with clopidogrel protects against impairment of autoregulatory behavior and renal vascular injury in ANG II-induced hypertension, possibly by reducing renal T cell infiltration.

Tocolytic indomethacin: effects on neonatal haemodynamics and cerebral autoregulation in the preterm newborn

BackgroundIndomethacin has vasoactive properties in cerebral and systemic vascular beds, and it improves cerebral autoregulatory ability. We speculated that tocolytic indomethacin will improve cerebral autoregulatory ability in the very preterm...

Cerebral Oxygenation, Extraction, and Autoregulation in Very Preterm Infants Who Develop Peri-Intraventricular Hemorrhage

To test the hypothesis that near-infrared spectroscopy (NIRS)-determined patterns of regional cerebral oxygen saturation (rScO2), cerebral fractional tissue oxygen extraction (cFTOE), and autoregulatory ability can identify neonates at risk for developing peri-intraventricular hemorrhage (PIVH). This case-control study is a subanalysis of 30 neonates who developed PIVH >12 hours after admission as part of a lager prospective observational cohort study comprising 650 preterm neonates born at ≤32 weeks' gestational age. PIVH was diagnosed by cranial ultrasound, performed at least once daily. Mean arterial blood pressure (MABP), NIRS-determined rScO2, cFTOE, and MABP-rScO2 correlation were monitored from birth to 72 hours of age. Infants with PIVH received more inotropic drugs before being diagnosed with PIVH. Significantly more infants with severe PIVH needed treatment for patent ductus arteriosus. The MABP-rScO2 correlation was >0.5 significantly more often before mild/moderate PIVH and after severe PIVH compared with controls. rScO2 was higher and cFTOE lower in infants before severe PIVH. NIRS-monitored rScO2 and cFTOE suggest cerebral hyperperfusion in infants with severe PIVH. Moreover, MABP-rScO2 correlation indicates more blood pressure-passive brain perfusion in infants with PIVH. Continuous assessment of patterns of cerebral oxygenation and arterial blood pressure may identify those preterm infants at risk for severe PIVH and prompt consideration of preventive measures.

Oxygen distribution in the retina

AbstractPurpose To evaluate the distibution of the preretinal and transretinal partial pressure of oxygen(PO2) in normal and ischemic retinas.Methods Evaluation of either the preretinal or intraretinal oxygen partial pressure (PO2) distribution, using oxygen sensitive microelectrodes, in normal or ischemic retinal conditions.Results The distribution of PO2 close to the vitreoretinal interface is heterogeneous, being higher near the arteriolar wall. Preretinal and transretinal PO2 profiles indicate that O2 diffusion from the arterioles affects the PO2 in the juxta‐arteriolar preretinal region. Both the preretinal and inner retinal PO2 recorded far from the vessels remain constant in all retinal areas. The oxygen tension (PO2) in the inner half of the retina remains largely unaffected by moderate changes in perfusion pressure, systemic PaO2 changes occuring during either hyperoxia or hypoxia. However, an increase in PaCO2 (hypercapnia), as well as an intravenous injection of acetazolamide (carbonic anhydrase inhibitor) both lead to an increase in preretinal PO2 due to dilation of the retinal vessels. In eyes with experimental branch retinal vein occlusion, PO2 values within the inner retinal layers are indicative of hypoxic conditions, whereas adjacent areas appear to remain normal. In diabetic patients undergoing vitrectomy a lowered vitreal PO2 in the affected retinal areas has also reported.Occlusion of the retinal circulation renders most of the inner retina anoxic.Conclusion Thanks to the autoregulatory ability of the retinal circulation, the oxygen tension (PO2) in the inner half of the retina, remains largely unaffected during physiological stimuli. In both normal and inner retinal ischemic conditions,the oxygen supply from the choroid is sufficient to support only the photoreceptor inner segments.

Can ambulatory blood pressure serve as a biomarker for presence of chronic kidney disease?

Can ambulatory blood pressure serve as a biomarker for presence of chronic kidney disease?

Disturbed correlation between arterial resistance and pulsatility in glaucoma patients

(i) To investigate whether pulsatility index (PI) and mean flow velocities (MFV) are altered in glaucoma patients. (ii) To evaluate the significance of PI in retrobulbar autoregulation capacity. Patients with primary open-angle glaucoma (POAG; n = 49), normal tension glaucoma (NTG; n = 62) and healthy controls (n = 48) underwent colour Doppler imaging measurements of the retrobulbar vasculature. Kruskal-Wallis test was used to compare variables between the three diagnostic groups. Restricted cubic splines were used to determine nonlinearities between the resistive index (RI) and PI correlations. Mean flow velocities (MFV) were lower in both short posterior ciliary arteries (SCPA) and central retinal arteries (CRA) from the two glaucoma groups (p < 0.04 versus healthy controls). No differences were detected in RI or PI in any arteries of the three diagnostic groups (p > 0.08). In healthy individuals, correlations between RI and PI were linear in all arteries. In both POAG and NTG patients, CRA presented a nonlinear curve with a cutpoint at RI 0.77 (p < 0.001) and 0.61 (p = 0.03), respectively, above which the slope increased nearly five- and tenfold (POAG: 1.96 to 10.06; NTG: -0.46-4.06), respectively. A nonlinear correlation in the ophthalmic artery was only observed in NTG patients, with a cutpoint at RI 0.82 (p < 0.001), above which the slope increased from 3.47 to 14.03. Glaucoma patients do not present the linear relationships between RI and PI observed in healthy individuals. Their nonlinear relations may be indicative of an altered autoregulation and suggest a possible threshold RI could be determined above which autoregulatory disturbances become more relevant.

Cerebral Oxygen Supply Monitored by Near Infrared Spectroscopy (NIRS) in the First Days of Life in Preterm Infants after Maternal Use of Labetolol

Background and aims: The aim of management of severe preeclampsia is to improve neonatal outcome and to prevent maternal complications. Antihypertensive treatment improves maternal outcome but has the potential to be deleterious. Maternal hypertension and preeclampsia can cause fetal IUGR and brainsparing. Although effects are to be expected from maternal use of beta blockers, scarce information on neonatal cerebral hemodynamics is available. Labetolol-induced changes in blood pressure (MABP) may influence regional cerebral saturation (rScO2). Methods: 18 infants with GA < 32 weeks, born after maternal use of labetolol (ML-group) were included and matched for GA, birth weight (BW) and gender (C-group). Arterial oxygen saturation, MABP, heart rate (HR) and rScO2 were monitored and an average was calculated on day 1 and 2. Results: GA, BW, respiratory support, use of inotropics and incidence of IVH did not differ between groups. Antenatal brainsparing was more prevalent in the ML-group (P< 0.05). HR was significantly lower in the ML-group in the first 48 hours but was always within normal limits (144 BPM ± 10.5 vs 152 BPM ± 10.7, p< 0.001). MABP was not different at all time points. rScO2 was significantly higher in the ML group (68 ± 10 vs 62 ± 9, p< 0.001). Conclusions: Despite lower HR in infants of preeclamptic mothers treated with labetolol cerebral oxygenation seems not to be compromised. Brainsparing seems to be associated with a higher oxygen delivery in the brain probably due to vasodilation and/or loss of autoregulatory ability of the cerebral vascular bed.

Cerebrovascular autoregulation among very low birth weight infants

Despite advances in neonatal care, intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) remain significant morbidities in very low birth weight infants. Disturbed cerebral hemodynamics may be a major contributor to the pathogenesis of these lesions.1, 2 A growing body of literature describes cerebral autoregulation among at-risk very low birth weight infants, including an eloquent study by Gilmore et al.,3 which describes the autoregulatory ability of preterm infants over the first 3 days of life—at the time they are most vulnerable to perinatal brain injury.

Renal hyperperfusion injury resulting in transient proteinuria post renal artery angioplasty for fibromuscular dysplasia

Renovascular hypertension (RVH) can be treated utilizing medical, surgical or endovascular techniques. We present a case in which severe exacerbation of pre-existing proteinuria followed percutaneous transluminal angioplasty of a highly stenotic renal artery to relieve RVH caused by fibromuscular dysplasia. We propose that the worsening proteinuria post-angioplasty was caused by a transient renal hyperperfusion injury that overcame the glomerular autoregulatory mechanisms, thereby leading to raised intraglomerular pressures and loss of proteins through the glomerular filtration barrier until the vascular autoregulatory ability of the glomeruli was successfully re-established.

Effect of a Phosphodiesterase 5 Inhibitor on Pulmonary and Cerebral Arteries of Newborn Piglets with Chronic Hypoxia-Induced Pulmonary Hypertension

Background: The use of phosphodiesterase 5 (PDE5) inhibitors to treat newborns with pulmonary hypertension is increasing. The effect of PDE5 inhibitors on the neonatal cerebral circulation remains unknown. The neonatal piglet model of chronic hypoxia-induced pulmonary hypertension allows the study of the effects of PDE5 inhibitors on both the pulmonary and cerebral circulations. Objectives: To determine whether the PDE5 inhibitor, zaprinast, causes dilation in pulmonary and middle cerebral arteries (MCA) of normoxic newborn piglets and those with chronic hypoxia-induced pulmonary hypertension, and to evaluate whether zaprinast alters responses to increased pressure (autoregulatory ability) of the MCA. Methods: Two-day-old piglets were raised in normoxia or hypoxia for 3 or 10 days. Pulmonary arteries and MCA were isolated and pressurized, after which changes in diameter to zaprinast were measured. MCA pressure-diameter relationships were determined. Results: Dilation to zaprinast was similar in pulmonary arteries from normoxic and hypoxic piglets. Zaprinast dilated MCA from all groups but the response was diminished in MCA from piglets raised in hypoxia for 10 days. MCA pressure-diameter relationships (autoregulation) did not differ between the groups. Conclusions: Pulmonary artery dilation to zaprinast supports the use of PDE5 inhibitors to treat pulmonary hypertension in neonates. PDE5 inhibitors function as MCA dilators but do not impair the pressure-diameter behavior of the cerebral circulation of either normoxic newborn piglets or those with chronic hypoxia-induced pulmonary hypertension. These findings suggest that cerebral autoregulation is likely to be intact with acute PDE5 inhibitor treatment in infants with pulmonary hypertension in conditions associated with chronic hypoxia.

Role of CD44+Stem Cells in Mural Cell Formation in the Human Choroid: Evidence of Vascular Instability Due to Limited Pericyte Ensheathment

To examine mural cell differentiation and pericyte ensheathment during human choroidal vascular formation and into adulthood. Triple- and double-labeled immunohistochemistry (alpha-smooth muscle actin [αSMA], desmin, NG2, calponin, caldesmon, CD44, CD34, and CD39) were applied to human fetal (8-32 weeks' gestation) and adult choroidal and retinal wholemounts and histologic cross-sections. Transmission electron microscopy (TEM) was also undertaken. Early in development CD44+ stem cells also stained with αSMA and CD39, suggesting a common precursor. At 12 weeks' gestation, αSMA+ mural precursor cells, confirmed by TEM, were found scattered and isolated over the primordial vascular tree. During development, αSMA+ cells formed a continuous sheath around large arterioles; in veins there were gaps in αSMA expression. The choriocapillaris had an extensive vascular bed but limited coverage by αSMA+ and NG2+ mural cells. Calponin was expressed only on large vessels, and no caldesmon was detected. Pericyte ensheathment of adult capillaries was 11% for choroid versus 94% for retina. Remarkably, choroidal pericytes had no visible intermediate filaments (IFs) on TEM, though IFs were present in retinal pericytes. Neither retinal nor choroidal pericytes stained with desmin. CD44+ stem cells are involved in the formation of mural cells in the human choroidal vasculature. A marked reduction in pericyte ensheathment of human choroidal vessels suggests a permanently open "plasticity window" and a predisposition to vascular instability and poor autoregulatory ability.

P2X1receptor blockade inhibits whole kidney autoregulation of renal blood flow in vivo

In vitro experiments demonstrate that P2X(1) receptor activation is important for normal afferent arteriolar autoregulatory behavior, but direct in vivo evidence for this relationship occurring in the whole kidney is unavailable. Experiments were performed to test the hypothesis that P2X(1) receptors are important for autoregulation of whole kidney blood flow. Renal blood flow (RBF) was measured in anesthetized male Sprague-Dawley rats before and during P2 receptor blockade with PPADS, P2X(1) receptor blockade with IP5I, or A(1) receptor blockade with DPCPX. Both P2X(1) and A(1) receptor stimulation with alpha,beta-methylene ATP and CPA, respectively, caused dose-dependent decreases in RBF. Administration of either PPADS or IP5I significantly blocked P2X(1) receptor stimulation. Likewise, administration of DPCPX significantly blocked A(1) receptor activation to CPA. Autoregulatory behavior was assessed by measuring RBF responses to reductions in renal perfusion pressure. In vehicle-infused rats, as pressure was decreased from 120 to 100 mmHg, there was no decrease in RBF. However, in either PPADS- or IP5I-infused rats, each decrease in pressure resulted in a significant decrease in RBF, demonstrating loss of autoregulatory ability. In DPCPX-infused rats, reductions in pressure did not cause significant reductions in RBF over the pressure range of 100-120 mmHg, but the autoregulatory curve tended to be steeper than vehicle-infused rats over the range of 80-100 mmHg, suggesting that A(1) receptors may influence RBF at lower pressures. These findings are consistent with in vitro data from afferent arterioles and support the hypothesis that P2X(1) receptor activation is important for whole kidney autoregulation in vivo.

Effects of 5-hydroxytryptamine on the cerebral blood flow in the dog.

The cerebrovascular response to intravenously infused 5-hydroxytryptamine was studied in anaesthetized dogs with the radioactive inert gas elimination technique with external γ-registration. A strong vasoconstrictory effect was found, which could not be abolished by either metysergide or alpha-blockade. The autoregulatory ability was found to be preserved. Even during arterial hypoxia, which has led to vasodilatation serotonin constricts the cerebral vessels.